The present invention relates to methods for treating various dermatoses including transient acantholytic dermatitis, acne miliaris necrotica, acne varoliformis, perioral dermatitis, and acneiform eruptions.
Transient acantholytic dermatitis, acne miliaris necrotica, acne varoliformis, perioral dermatitis, and acneiform eruptions are common dermatological diseases. Each of the dermatoses has its own etiology and histology.
1. Transient Acantholytic Dermatosis
Transient acantholytic dermatosis, also called syn Grover""s disease, is an acquired skin disease which is seen as itchy papules and vesicles resulting in soreness over the area. The lesions appear on the shoulders, neck, thighs, scalp rapidly. Some of the papules can become rough and may have crusting. The disease mostly occurs in meddle to old age, especially in men. Unlike the name of the disease, the condition is not transient, and can last for years.
The cause of the disease is unknown, however, various factors are thought to precipitate the disease, including sun exposure and sun burn, heat exposure, sweating, fever, radiation treatment, and cancers. There is no specific treatment for this disease. Currently, topical steroids, systemic steroids, oral vitamin A, etretinate, PUVA (psoralen and long-wave ultraviolet radiation) and Accutane(copyright) (isotretnoin, manufactured by Roche) have been used clinically.
2. Acne Miliaris Necrotica and Acne Varioliformis
Acne miliaris necrotica, also called scalp folliculitis, consists of follicular vesicopustules, frequently solitary, usually very itchy and tender, which appear anywhere in the scalp or adjacent areas. It can range from an occasional nuisance that many people experience to a chronic problem that can be quite troublesome. The severe form of the disease which leaves large scars is called acne varioliformis. The condition is more common in people who are doing activities that make them sweat or who wear occlusive head gear. Stress often seems to trigger outbreaks as well. Existing treatments range from antibiotic shampoos such as Capitrol(copyright) (a chloroxine shampoo), astringent compresses, topical antibiotics or steroids to oral antibiotics. In extreme cases, Accutane(copyright) has been used, which is well known for the severe adverse side effects that can cause.
3. Perioral Dermatitis
Perioral dermatitis is a chronic papulopustular facial dermatitis. It mostly occurs in younger women. The incidence is estimated as 0.5-1% in industrialized countries, independent of geographical factors. The disease is limited to the skin. Skin lesions occur as grouped follicular reddish papules, papulovesicles and papulopustules on erythematous base with a possible confluent aspect. In an extreme variant of the disease, called lupuslike perioral dermatitis, granulomatous infiltrates occur with a yellowish aspect in diascopy. Although perioral dermatitis is limited to the skin and not life threatening, emotional problems may occur due to the disfiguring character of the facial lesions and a possible prolonged course of the disease.
The etiology of perioral dermatitis is unknown. However, many causative factors have been suggested, including injudicious use of topical steroids, fluorinated toothpaste, skin care ointments and creams, especially with a petrolatum or paraffin base and the vehicle isopropyl myristate, and old or contaminated make-up or applicators. It is known that UV light, heat and wind worsen perioral dermatitis. Further, microbials such as fusiform spirilla bacteria, candida species and other fungi have been found from the lesions. Other microbiological factors, such as candidiasis have been reported to provoke perioral dermatitis. In addition, hormonal factors, and gastrointestinal disturbances have been considered as well.
Known treatments include oral tetracyclines, minocin and do3cycline, with discontinuing topical corticosteroids, and avoiding lauryl sulfate toothpaste. However, it is currently believed there is no medicine that one can apply directly to the skin which will help perioral dermatitis.
4. Acneiform Eruptions
Acneiform eruptions are characterized by papules and pustules resembling acne lesions, not necessarily confined to the usual sites of acne vulgaris. The eruptions are distinguished by their sudden onset, usually in a patient well past adolescence. Most of the acneiform eruptions originate from skin exposure to various industrial chemicals. Some eruptions may come from oral medications. Acneiform eruptions may be induced by exposure of the skin to the fumes generated in the manufacture of chlorine and its by-products. Cutting oils, lubricating oils, crude coal tar applied to the skin for medicinal purposes, have tar distillates, coal tar pitch, and corticosteroids applied to the skin under occlusive dressings, and asbestos are known substances that may produce acneiform eruptions. Some of the acneiform eruptions are induced by medications such as iodides in vitamins with mineral supplement, and bromides in drugs such as propantheline bromide, and corticosteroids.
Although commonly called xe2x80x9ctrade acnexe2x80x9d, xe2x80x9cbromine acnexe2x80x9d, and xe2x80x9cchloracnexe2x80x9d, acneiform eruptions are not a true acne, even though they are often ushered in by open comedones. Current treatments of acneiform eruptions include massive keratinization-suppressing doses of vitamin A, 300,000 units daily, topical retinoids, such as Retin-A cream or gel, or even oral Accutane(copyright).
The above-discussed dermatoses are commonly seen clinically. Some patients respond well to the existing treatments. However, many patients suffer from the diseases for many years without significant improvement after being treated with all existing treatments. Furthermore, some patients have adverse reactions to the existing medications, or can not tolerate antibiotics used for treating these dermatoses. Sometimes, it is not appropriate to use existing treatment methods or medications for certain patients. For example, antibiotics and Accutane(copyright) are effective for treating acute inflammation caused by these dermatoses, however, they should not be used for pregnant women and nursing mothers. Therefore, there is apparently a need for new and effective topical treatments for the above-menboned dermatoses.
The preferred compound that is used to illustrate the present invention is ivermectin. Ivermectin is a semi-synthetic derivative of avermectin and is generally produced as a mixture of at least 80% 22,23-dihydroavermectin B1a and less than 20% 22,23-dihydroavermectin B1b. The following molecular structure represents the avermectin series of compounds, which can be chemically converted to useful derivatives as discussed below. 
wherein R is the 4xe2x80x2-(alpha-L-oleandrosyl)-alpha-L-oleandrose group of the structure: 
wherein the broken line indicates a single or double bond; R1 is hydroxy and is present only when said broken line indicates a double bond; R2 is isopropyl or sec-butyl; and R3 is methoxy or hydroxy.
The avermectins, of which ivermectin, a chemically produced along, is a member are a series of compounds isolated from the fermentation broth of a C-076 producing strain of Streptomyces avermitillis and also chemically produced derivatives thereof. There are eight different but closely related compounds are produced by S. avermitillis, designated as A1a, A1b, A2a, A2b, B1a, B1b, B2a, and B2b. The production of these compounds is described in U.S. Pat. No. 4,310,519. The preparation of ivermectin is disclosed in U.S. Pat. No. 4,199,569. The disclosures of each of the foregoing patents are incorporated herein by reference. The avermectin family of compounds is a series of very potent antiparasitic agents known to be useful against a broad spectrum of endoparasites and ectoparasites in mammals and also to have agricultural uses against various nematode and insect parasites found in and on crops and in soil.
Some of the avermectins contain a 22,23-double bond. This may be selectively reduced to prepare the ivermectin compounds. In addition, the avermectins possess a disaccharide moiety at the 13-position consisting of the alpha-L-oleandrosyl-alpha-L-oleandrosyl group. One or both of these saccharide groups may be removed as described in U.S. Pat. No. 4,206,205, and the produced aglycone derivatives have a hydroxy group at the 13-position. This group may be removed to form the 13-deoxy compound as described in U.S. Pat. Nos. 4,171,314 and 4,173,571; the latter patent also describes the 13-halo derivatives. The avermectin compounds and derivatives have several hydroxy groups which may be acylated as described in U.S. Pat. No. 4,201,861. U.S. Pat. No. 5,055,454 describes invert position 13 of avermectin from a normal alpha stereochemistry to the epimeric 13-beta stereochemistry. U.S. Pat. No. 5,077,308 describes avermectin aglycone derivatives which incorporate a ketal at position 13. U.S. Pat. No. 5,162,363 describes avermectin derivatives where the 23-position ring carbon atom is replaced with by sulfur atom. U.S. Pat. No. 5,229,416 describes avermectin aglycone derivatives which incorporate two fluorine atoms at position 13 and 23. U.S. Pat. No. 5,262,400 describes avermectin compounds that have various substituents at the 4a-position including alkyl, alkoxy alkyl, or polyalkoxy alkyl groups. Other derivatives of avermectin and ivermectin are disclosed in U.S. Pat. Nos. 4,333,925, 4,963,667, 5,114,930, 5,350,742, and 5,830,875. All the aforementioned patents are incorporated herein by reference. The compounds disclosed in the patents mentioned above share the property of antiparasitic activity with ivermectin.
All avermectin compounds mentioned and referred to above share the spectrum of anti-parasitic biological activity of ivermectin, varying only in degree. It is expected that they will share the activity spectrum of ivermectin needed for them being suitable to use for the purpose of the present invention.
Ivermectin has been used as an antiparasitic agent to treat various animal parasites and parasitic diseases since mid-1980""s. It is commercially available for animal use as Cardomec (for felines), Eqvalan (for equines) and Ivomec (for bovines) by Merial, a company of Merck Sharp and Dohme and Aventis. The medicine is available in tablets and chewables for heartworm prevention, topical solution for ear mite treatment, or as oral or injectable solution for other parasite problems.
Ivermectin is also commercially available from Merck and Co., Inc for human use as Stromectol(copyright) for eradication of threadworm Strongyloides stercoralis, and for eradication of Onchocerca volvulus. Stromectol(copyright) was approved by the U.S. Food and Drug Administration to treat nondisseminated intestinal threadworm (strongyloidiasis) in March 1997. Stromectol(copyright) has also been cleared by the U.S. Food and Drug Administration to treat onchocerciasis, or river blindness. The medicine is available in tablets and is orally administered by the patients. The recommended dose of Stromectol(copyright) for the treatment of intestinal strongyloidiasis is a single oral dose, two 6 mg tablets for average weight adults (200 micrograms per kilogram of body weight). Stromectol(copyright) can also be used in children who weigh 15 kg (33 lb.) or more, at a dose ranging from xc2xd to 2 tablets.
Magda et al. Amer. J. Trop. Med. Hyg. 53(6) 1995 pp. 652-653 describe a method of topical application of ivermectin to treat head lice. Ivermectin is found to have an absolute curative effect after a single topical application.
U.S. Pat. No. 5,952,372 (to McDaniel) discloses a method of treating a form of rosacea associated with the ectoparasite Demodex by orally administering or topically applying ivermectin to fill and eliminate Demodex Follicuorum mites from hair follicles in affected skin. Such treatment results in cessation of the manifestations of allergic and vasomotor responses to the organism that cause the symptoms and signs of rosacea.
U.S. Pat. No. 6,133,310 (to Parks) discloses a method of treating acne rosacea by topically applying ivermectin to the affected areas. Acne rosacea is a different dermatological disease, in term of etiology, and/or histology, from transient acantholytic dermatitis, acne miliaris necrotica, acne varioliformis, perioral dermatitis, and acneiform eruptions addressed in the present invention. Differential diagnosis is important for the patients to obtain an appropriate treatment and effective prevention of their conditions.
Accordingly, it is an object of the invention to provide an effective topical treatment of transient acantholytic dermatitis, acne miliaris necrotica, acne varioliformis, perioral dermatitis, and acneiform eruptions.
In one embodiment, the present invention relates to a method of treating a dermatosis comprising topically applying a therapeutically effective amount of an avermectin compound to an affected area of a patient. The dermotosis is one disease selected from the group consisting of transient acantholytic dermatitis, acne miliaris necrotica, acne varioliformis, perioral dermatitis, and acneiform eruptions.
The avermectin compound is in a dermatological composition comprising an effective amount of the avermectin compound and a pharmaceutically acceptable carrier including water, glycols, alcohols, lotions, creams, gels, emulsions, sprays, shampoos, soaps, body washes, facial cleansers, and facial masks. The dermatological composition can also be integrated into medicated tape, topical dressing, dermal patch, or cleansing tissue. The avermectin compound includes avermectins, avermectin derivatives, ivermectin and ivermectin derivatives. The concentration of the avermectin compound in the dermatological composition is from about 0.05% to about 8% (w/v). In a preferred embodiment, ivermectin is used.
In a further embodiment, the present invention relates to a method of treating a dermatosis selected from the group consisting of transient acantholytic dermatitis, acne miliaris necrotica, acne varioliformis, perioral dermatitis, and acneiform eruptions comprising the steps of: (a) topically applying an initial dosage of an avermectin compound to an affected area of a patient for an initial treatment period, and (b) thereafter topically applying a maintenance dosage of an avermectin compound to the affected area for maintenance.
In an additional embodiment, the present invention further relates to a dermatological kit for treating treating transient acantholytic dermatitis, acne miliaris necrotica, acne varioliformis, perioral dermatitis, or acneiform eruptions. The kit includes a dermatological composition comprising avermectin compound and a pharmaceutically acceptable carrier in a container, and an insert, on or inside of said container, with instructions on how to use the dermatological composition for treating transient acantholytic dermatitis, acne miliaris necrotica, acne varioliformis, perioral dermatitis, and acneiform eruptions.
The present invention relates to a method of treating several common dermatoses including transient acantholytic dermatitis, acne miliaris necrotica, acne varioliformis, perioral dermatitis, and acneiform eruptions. The method comprises topical application of a therapeutically effective amount of an avermectin compound to affected areas of a patient.
The avermectin compounds for the purpose of the present invention include avermectin, avermectin derivatives, ivermectin, and ivermectin derivatives. The avermectin compound is preferably mixed with a pharmaceutically acceptable carrier or a base which is suitable for topical application to dermal tissues, to form a dermatological composition. Suitable examples of carrier or base include, but not limited to, water, glycols, alcohols, lotions, creams, gels, emulsions, and sprays. Furthermore, the dermatological composition containing an avermectin compound can be integrated into topic dressing, medicated tape, skin patch, also called dermal patch, and cleansing tissues. Additionally, the avermectin compound can be added into shampoo, soap, body wash, facial cleanser, and facial mask. Examples 1 to 3 provide various topical dermatological compositions containing an avermectin compound for treatment of the above-referenced dermatoses.
In a preferred embodiment, ivermectin is used because it is readily available commercially. The concentration of ivermectin in the dermatological composition for the purpose of the present invention can be in a broad range from about 0.05% to 8% weight by volume (w/v). It has been found that a lotion or a cream containing ivermectin at a concentration as low as 0.075% is clinically effective in treating transient acantholytic dermatitis, acne miliaris necrotica, acne varioliformis, perioral dermatitis, and acneiform eruptions.
The treatment method using ivermectin dermatological composition for each of these dermatoses is similar. Preferably, in an initial treatment of these dermatoses the ivermectin dermatological composition can be applied topically from one to several times daily for a period of from about one week to several weeks, to substantially control the condition and clear the lesions. The initial dosage, including frequency of the topical application, ivermectin concentration of the dermatological composition, and the length of the initial treatment period can be determined depending on a specific disease, severity of the disease, and the response of the patient to the medication. For example, acne miliaris necrotica is more difficult to treat, and it frequently requires an initial treatment of three weeks or longer. While perioral dermatitis patients can respond to ivermectin treatment rapidly, and healing of lesions can occur in less than two weeks. After the initial treatment, a maintenance dosage, that has less frequent application, and/or a dermatological composition with less concentration of ivermectin, can be used for maintaining the condition.
It has been found in an informal clinical trial using the method of the present invention that topical application of ivermectin to skin affected by transient acantholytic dermatitis, acne miliaris necrotica, acne varioliformis, perioral dermatitis, or acneiform eruptions has the following advantageous properties: (1) it removes itching and skin irritation caused by these dermatoses; (2) it clears up lesions; (3) it is anti-inflammatory and controls inflammation of the affected area; (4) it has antimicrobial property and controls dermal infection of the affected area; and (5) it is safe and has no side effects observed in any body locations.
The choice of the ivermectin concentration, and the form of the dermatological composition for treatment of a particular condition of the above-referenced dermatoses can be made depending on the type and severity of the diseases, location of the affected area, and form of the dermatological composition.
To treat most patients diagnosed with one of the above-mentioned dermatoses, a lotion containing about 0.05% to 0.2% of ivermectin can be used. In the case of treating acute conditions, a more potent composition containing higher concentration of ivermectin can be used. On the other hand, for prolonged maintenance of certain conditions, a low concentration such as from about 0.05% to about 0.1% is preferred. Further, a low concentration of ivermectin should be used for pediatric patients.
It is known that some of the diseases, such as perioral dermatitis, the skin on the eyelids can be affected. To treat eyelids, a high concentration of the medicine should be avoided to prevent irritation of the eyes. It is found that a 0.075% ivermectin lotion does not cause eye irritation when it is used on the face, around the eyes, or directly on the eyelids.
In the form of shampoo, soap, facial cleanser, and facial mask the concentration of ivermectin is higher, such as about 2% to about 8%, because the medicine is not retained on the skin after rinsing, and treatment time is short. On the contrary, in the forms of topic dressing, medicated tape, and dermal patch the medicine stays on the treated area longer than other forms, therefore, the concentration of ivermectin can be lower.
The ivermectin shampoo is an appropriate form for treating transient acantholytic dermatitis, acne miliaris necrotica and acne varioliformis, when the affected area is on the scalp. The medicated shampoo can be particularly suitable for maintenance treatment, or prevention of break out for the patients who have chronical history of these diseases.
Optionally, a combination of different forms of topical treatment can also be used. For example, an ivermectin tape can be used in the night, and an ivermectin cream or lotion can be used during the day. The ivermectin shampoo, soap, facial cleanser, and facial mask can be used in combination with any of other topical applications.
The dermatological composition containing ivermectin can be sold as a kit wherein the composition is packaged in a container, such as a plastic container. Instructions on how to use the dermatological composition in accordance with the present invention are included on or associated with the container, which provides detailed instructions for treating transient acantholytic dermatitis, acne miliaris necrotica, acne varioliformis, perioral dermatitis, or acneiform eruptions.
Although the inventor is not bound by any theoretical explanation as to why the composition and the method of the present invention are effective in treating transient acantholytic dermatitis, acne miliaris necrotica, acne varioliformis, perioral dermatitis, or acneiform eruptions, presentation of certain theoretical understanding may be of value. Based on the clinical observations, it is believed that one reason for the efficacy of the composition and the method of the present invention is due in part to anti-microbial property of ivermectin.
Another possible reason for the efficacy of the composition and the method of the present invention is that the ivermectin dermatological composition has anti-inflammatory effect. It is believed that ivermectin exerts an anti-inflammatory effect on the cells of the sebaceous gland unit, thus decreasing production of neutrophils and lymphocytes which contribute to inflammation.
Ivermectin has been used as an oral medication for treatment of river blindness in human caused by Onchocerca volvulus parasite since late 1980s. With an oral dosage of a moderate ivermectin concentration, this medicine is safe in human, without serious adverse side effects. Therefore, topical treatment of dermatoses using ivermectin dermatological composition and the method of the present invention is safe to human patients, which was demonstrated by the clinical examples described hereinafter. Furthermore, as discussed previously that a dermatological composition having ivermectin concentration as low as 0.075% is clinically effective in treating transient acantholytic dermatitis, acne miliaris necrotica, acne varioliformis, perioral dermatitis, and acneiform eruptions. Such a low concentration is advantageous because it reduces risks of adverse side effects, and reduces the possibility of triggering body""s autoimmune responses.